Posttranslational Acetylation of the Human Immunodeficiency Virus Type 1 Integrase Carboxyl-Terminal Domain Is Dispensable for Viral Replication

Topper, Michael; Luo, Yang; Zhadina, Maria; Mohammed, Kevin; Smith, Leonard A.; Muesing, Mark A.

doi:10.1128/jvi.02257-06

Cited by 44 publications

(55 citation statements)

References 42 publications

(36 reference statements)

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“…Several studies revealed that p300 preferentially acetylates stretches of lysine residues of substrate proteins (Bai et al, 2005;Faiola et al, 2007;Hasan et al, 2001b;Hassa et al, 2005;Topper et al, 2007). The RECQL4 amino-acid sequence contains 32 lysine residues, and the only lysine stretch is located in the previously Fig.…”

Section: Identification Of Acetylation Sites Of Recql4mentioning

confidence: 99%

p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization

Dietschy

Shevelev

Peña-Dı́az

et al. 2009

Journal of Cell Science

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RECQL4 belongs to the conserved RecQ family of DNA helicases, members of which play important roles in the maintenance of genome stability in all organisms that have been examined. Although genetic alterations in the RECQL4 gene are reported to be associated with three autosomal recessive disorders (Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes), the molecular role of RECQL4 still remains poorly understood. Here, we show that RECQL4 specifically interacts with the histone acetyltransferase p300 (also known as p300 HAT), both in vivo and in vitro, and that p300 acetylates one or more of the lysine residues at positions 376, 380, 382, 385 and 386 of RECQL4. Furthermore, we report that these five lysine residues lie within a short motif of 30 amino acids that is essential for the nuclear localization of RECQL4. Remarkably, the acetylation of RECQL4 by p300 in vivo leads to a significant shift of a proportion of RECQL4 protein from the nucleus to the cytoplasm. This accumulation of the acetylated RECQL4 is a result of its inability to be imported into the nucleus. Our results provide the first evidence of a post-translational modification of the RECQL4 protein, and suggest that acetylation of RECQL4 by p300 regulates the trafficking of RECQL4 between the nucleus and the cytoplasm.

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Section: Identification Of Acetylation Sites Of Recql4mentioning

confidence: 99%

p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization

Dietschy

Shevelev

Peña-Dı́az

et al. 2009

Journal of Cell Science

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“…It has recently been shown that the HIV-1 IN CTD is a potent substrate for p300-mediated histone acetyltransferase (HAT) activity (10,70) at three lysine residues (K264, K266, and K273), a phenomenon subsequently demonstrated to be nonessential for sustained viral replication through an immortalized T cell line (70). Interestingly, K273 may also be targeted for posttranslational ubiquitinylation (61).…”

mentioning

confidence: 99%

Sequential Deletion of the Integrase (Gag-Pol) Carboxyl Terminus Reveals Distinct Phenotypic Classes of Defective HIV-1

Mohammed

Topper

Muesing

2011

J Virol

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A requisite step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is the insertion of the viral genome into that of the host cell, a process catalyzed by the 288-amino-acid (32-kDa) viral integrase (IN). IN recognizes and cleaves the ends of reverse-transcribed viral DNA and directs its insertion into the chromosomal DNA of the target cell. IN function, however, is not limited to integration, as the protein is required for other aspects of viral replication, including assembly, virion maturation, and reverse transcription. Previous studies demonstrated that IN is comprised of three domains: the N-terminal domain (NTD), catalytic core domain (CCD), and C-terminal domain (CTD). Whereas the CCD is mainly responsible for providing the structural framework for catalysis, the roles of the other two domains remain enigmatic. This study aimed to elucidate the primary and subsidiary roles that the CTD has in protein function. To this end, we generated and tested a nested set of IN C-terminal deletion mutants in measurable assays of virologic function. We discovered that removal of up to 15 residues (IN 273) resulted in incremental diminution of enzymatic function and infectivity and that removal of the next three residues resulted in a loss of infectivity. However, replication competency was surprisingly reestablished with one further truncation, corresponding to IN 269 and coinciding with partial restoration of integration activity, but it was lost permanently for all truncations extending N terminal to this position. Our analyses of these replication-competent and -incompetent truncation mutants suggest potential roles for the IN CTD in precursor protein processing, reverse transcription, integration, and IN multimerization.The defining hallmarks of retroviruses are reverse transcription of the viral genomic information as encoded in polyadenylated RNA and the subsequent integration of the copied DNA genome into that of a host cell. The latter is an essential and irreversible event which is mediated by the catalytic activities of the viral integrase protein (IN), the recent target of successful chemotherapeutic intervention against HIV-1 infection (1). HIV-1 IN is a 288-amino-acid, 32-kDa protein that is cleaved from the C terminus of the Gag-Pol polyprotein (Pr160 Gag-Pol ) via viral proteolytic activity. The biochemical mechanisms that lead to retroviral integration, which have been extensively studied in vitro, are defined by two catalytically related and sequentially dependent steps (18) which may be distinguished by their respective sensitivities to current inhibitors of IN function (39). Following the completion of reverse transcription of the viral RNA into its DNA copy, IN removes two nucleotides from the 3Ј end of each strand of the viral DNA. This step, termed 3Ј processing, generates a chemically reactive 3Ј-hydroxyl group (CA OH -3Ј) at the 3Ј ends of the DNA molecule, effectively activating the termini for the subsequent reaction (strand transfer). This enzymatic step is the target of all I...

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“…A recent study from the same group showed that another HAT, GCN5, was also able to mediate the acetylation of HIV-1 IN, and provirus formation was inefficient in GCN5-depleted cells (Terreni et al, 2010). However, it should be noted that the role of acetylation of IN in HIV-1 replication remains controversial (Topper et al, 2007;. Another type of posttranslational modification of IN that regulates HIV-1 infection has also been demonstrated.…”

Section: Cellular Interactors Affecting On Integration Stepmentioning

confidence: 99%

Molecular Crosstalk between HIV-1 Integration and Host Proteins – Implications for Therapeutics

Suzuki¹,

Suzuki²,

Yamamoto³

2011

HIV-Host Interactions

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Posttranslational Acetylation of the Human Immunodeficiency Virus Type 1 Integrase Carboxyl-Terminal Domain Is Dispensable for Viral Replication

Cited by 44 publications

References 42 publications

p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization

p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization

Sequential Deletion of the Integrase (Gag-Pol) Carboxyl Terminus Reveals Distinct Phenotypic Classes of Defective HIV-1

Molecular Crosstalk between HIV-1 Integration and Host Proteins – Implications for Therapeutics

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